Cognitive impairment has been identified as a type 2 diabetes (T2D) complication. T2D has consistently been associated with increased risk for dementia and cognitive decline. Our recent studies suggest biological mechanisms through which this risk can be remedied. Diabetic persons treated with both insulin and other hypoglycemic medications, but not with either agent alone, have significantly less Alzheimer's Disease (AD) neuropathology than matched non- diabetic persons. The insulin receptor signaling pathway (IRSP) is a promising and biologically plausible mechanism by which the treatment of diabetes with combination therapy might affect the neurobiological substrates of cognitive impairment and dementia in elderly persons with and without diabetes. Studies examining the brain IRSP in diabetes and AD show that its functioning is significantly altered. This study will build on the experience of the JJ Peters VAMC and Mount Sinai School of Medicine Brain Bank and the neurobiology laboratories at the JJP-VAMC. Brain gene (Aim 1) and protein (Aim 2) expression studies of several key mediators and effectors in the IRSP (e.g., IR, IGF-1R, IRS1, IRS2, AKT1-3, GSK3, FOXO1, and -Catenin), in postmortem brain specimens (superior temporal gyrus, hippocampus and occipital cortex), will compare diabetic subjects treated with combination therapy to matched diabetic subjects treated with insulin only, hypoglycemic medication only, and to non-diabetic subjects with and without AD-dementia. Relationships of expression alterations with cognitive-impairment-associated neuropathologies (A and tau) will also be explored (Aim 3). To establish cause and effect relationships we will compare 8 groups of mice: combination therapy, insulin, metformin, or neither, in Tg2576 mice fed a high fat diet to induce insulin resistance (AD and T2D mouse models) or WT. Identifying brain molecular-biological pathways affected in diabetes and altered/restored by combination therapy is crucial to the translation of clinicopathological result to the development of treatment strategies for cognitive compromise in elderly Veterans with and without diabetes and to the promotion of their successful aging. The public health impact of this investigation to our Veterans is highlighted by the increasing prevalences of both diabetes and dementia, which are expected to dramatically accelerate as the proportion of elderly Veteran increases.